Preparation of an active substance solution which can be sterili

Details Preparation of an active substance solution which can be sterili Preparation of an active substance solution which can be sterili

1994-01-13

1995-07-11

Brust, Joseph Paul

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

558390, A61K 31275

Patent

active

054321964

DESCRIPTION:

BRIEF SUMMARY
Active substances for parenteral administration must be formulated as aqueous solutions. Considerable problems often arise from the sparing solubility of many active substances. In such cases it is frequently possible to prepare an appropriate solution only with the aid of cosolvents (eg. ethanol) and/or solubilizers.
One example of a sparingly soluble active substance is anipamil hydrochloride (EP 64 158) whose solubility in water is below 10 mg/liter.
Although it is generally easy to prepare aqueous solutions of sparingly soluble active substances with the aid of synthetic solubilizers, the latter substances are often unusable because of their side effects, especially after intravenous administration.
By contrast, naturally occurring phospholipids are known to be tolerated virtually without reaction even after parenteral administration, inter alia because they are normal components of every cell membrane. These "natural" solubilizers are likewise suitable for preparing solutions for injection and infusion of sparingly soluble active substances. For parenteral nutrition, for example, the sparingly soluble fats required are formulated with the aid of phospholipids (egg lecithin or soybean lecithin) as an emulsion which can be administered in relatively large amounts without the side effects observed with synthetic solubilizers. Emulsions of this type are composed of fat droplets which are finely dispersed in water. It is also possible for sparingly soluble active substances to be bound to the fat droplets in such emulsions and then administered parenterally in the form of such colloidal solutions.
Solutions containing phospholipids are in principle considerably more difficult to prepare than solutions containing synthetic solubilizers. On dispersion in water, phospholipids do not form clear micellar solutions like synthetic solubilizers, but always only form cloudy colloidal solutions with particles several .mu.m in size. Products containing such large particles cannot be administered parenterally because there is too great a risk of embolism. This is why, when phospholipids are used as solubilizers, a homogenization, eg. a high-pressure homogenization, must be carried out to reduce the particle size to below 1 .mu.m. The expense of preparation is therefore distinctly higher when phospholipids are used as solubilizers because of the homogenization which is necessary.
We have now found a considerably simpler way to prepare anipamil-containing solutions.
The present invention relates to a process for preparing an aqueous anipamil solution which can be sterilized by filtration, which comprises mixing anipamil hydrochloride with a phospholipid in the ratio of from 1:2 to 2:1 by weight, converting the resulting mixture into a gel by adding water at elevated temperature while stirring, and subsequently adding water to the gel at elevated temperature until the active substance is present in the required concentration.
The process can be applied both to anipamil racemate and to the R and S enantiomers.
Suitable phospholipids are, inter alia, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylglycerol, either alone or in combination with one another. Phosphatidylcholines are preferred, especially those which contain unsaturated fatty acid residues, such as oleic acid and/or linoleic acid residues. Highly purified egg and soybean lecithins which contain at least 80% phosphatidylcholine are particularly preferred. Anipamil hydrochloride and phospholipid are mixed in a ratio of from 1:2 to 2:1, preferably from 1:1.5 to 1.5:1, in particular of about 1:1. Water is then added stepwise, while stirring, to the active substance/phospholipid mixture at about 50 .degree. -90.degree. C., preferably about 70.degree.-80.degree. C. The total amount of water added is about 20 ml per g of active substance/phospholipid mixture, adding 3-7 ml portions stepwise at intervals of 5-10 min. After formation of the gel it is necessary to dilute to the required concentration of active substance with more water

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Actions of verapamil analogues, anipamil and . . . ; Curtis et al., Br. J. Pharmac. (1986), 88, pp. 355-361.

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